The increased sensitivity to catecholamines in the diabetic state is well known in animal models of diabetes mellitus as well as in human diabetics. The objective of this research program is to elucidate the molecular mechanisms involved in the causation of this adrenergic supersensitivity in diabetes mellitus. Experiments will be carried out in animal models of diabetes mellitus as well as in blood elements obtained from patients with diabetes mellitus. The research program will be comprised of four major sections. The first section will deal with the regulation of a- and b-adrenergic receptors by insulin. The effect of streptozotocin induced diabetes on the levels of a- and b-adrenergic receptors will be studied in rat heart, blood vessels and liver. Besides the receptor number and affinity changes, the effect on steps subsequent to receptor activation will also be examined. The second section will deal with defining the relative roles of the absence of insulin or the presence of diabetic disease state in producing the observed alterations in the adrenergic sensitivity in diabetes mellitus. The a- and b-adrenergic receptor levels and function in hyperglycemic and hyperinsulinemic (C57BL/KsJ, 7-9 weeks old), hyperglycemic and hypoinsulinemic (C57BL/KsJ, 6-12 months old) and moderately hyperglycemic and hyperinsulinemic (C57BL/6J) mice heart, blood vessels and liver will be measured and compared. The third section of the research program will involve measuring and comparing platelet a- and lymphocyte b-adrenoceptor levels and the adrenergic receptor mediated subsequent biochemical responses in human blood samples obtained from patients with juvenile-onset diabetes, adult-onset diabetes and matched controls. Section IV of the research program will deal with defining in depth the coupling phenomenon between the adrenergic receptor and adenylate cyclase in human platelets and lymphocytes in samples from diabetics and matched controls. The research program should provide insights into some aspects of the pathophysiology of diabetes mellitus both at a molecular and clinical level.